Differential Diagnosis

• CF with sensitization to Af
• Bacterial, viral, fungal pneumonias
• Tuberculosis
• Acute/chronic eosinophilic pneumonia, drug-induced eosinophilic pneumonia, tropical (filarial) eosinophilic pneumonia
• Churg-Strauss syndrome
• Hypereosinophilic syndromes
• Loeffler's pneumonia (Ascariasis)
• Avian-hypersensitivity pneumonitis
• Autoimmune diseases (rheumatoid arthritis, pernicious anemia, and sarcoidosis)
• Complications of crack-cocaine abuse
• Asthma with sensitization to Aspergilus fumigatus (Af) sometimes described in the literature as SAFS "severe asthma with fungal sensitization" or AFAA "Af associated asthma"

Note:

• Differential for bronchiectasis includes ABPA, hypogammaglobulinemia, ciliary dysfunction, CF, or idiopathic causes
• Pulmonary diseases due to Aspergillus include disseminated aspergillosis, aspergilloma or mycetoma, allergic asthma, extrinsic allergic alveolitis (malt worker’s lung), and ABPA

Diagnosis

Clinical Parameters

• Occurs primarily in patients with:
  • Asthma (2-32% of asthma patients)
  • CF (1-15% of CF patients)
• The typical clinical picture of ABPA is asthma with recurrent episodes of bronchial obstruction, fever, malaise, brownish mucus plugs, serum eosinophilia, and sometimes hemoptysis. Wheezing is not always evident, and some patients present with asymptomatic pulmonary consolidation
• ABPA should be considered when patients are found to have asthma plus:
  • Bronchiectasis that is either non-CF or CF in nature
  • History of prior pneumonias or lobar or lung collapse
  • Sputum plugs
  • Evidence of anti-Af IgE antibodies either by skin testing or sIgE
  • Unexplained peripheral blood eosinophilia of 8-40%
  • Worsening severity of asthma
  • Pathologic diagnoses of mucoid impaction of the bronchi, bronchocentric granulomatosis, or both
• ABPA is less likely in patients with intermittent/mild asthma, asthma with AD, asthma with low total IgE
• Immunomodulators (e.g. etanercept) may be a risk factor for developing ABPA

1000 ng/mL = 417 IU/mL
1 IU/mL = 2.4 ng/mL

Evaluation

1. Skin test - A negative SPT followed by negative ID skin test to Af virtually excludes ABPA.
   • 20-30% of asthmatics have positive SPT to Af
   • Consider that SPT or ID may be negative due to poor quality of extract, or the Aspergillus mix extract may not contain Af
   • Some ABPA patients display a biphasic skin response to the ID (immediate wheal/flare seen within 20 min, which subsides, to be followed in 4-8 h by erythema/induration that resolves in 24 h)
2. If skin test positive, check serum total IgE and precipitins to Af
   • ABPA is excluded if total IgE is <417 IU/mL or if serum precipitins to Af are negative
     • IgE levels are typically elevated (sometimes markedly to 30,000 IU/mL) but may fall to <417 IU/mL (but generally do not normalize) if the patient is receiving glucocorticoids
     • Precipitating antibodies to Af can be detected in unconcentrated sera of 70–100% of ABPA patients
       • Presence of precipitins to Af is not specific to ABPA (demonstrated in 9% of hospitalized patients, 3% of healthy office workers, 12% of allergic asthmatic patients, 27% of patients with farmer’s lung, and practically all patients with aspergilloma)
3. If IgE >1000 IU/mL and the precipitin test is positive, a presumptive diagnosis of ABPA is made. Check specific anti-Af IgE and IgG: a two-fold elevation in anti-Af IgE and IgG indices (compared to pooled serum of Af-sensitized non-ABPA asthmatics) indicates seropositive ABPA rather than sensitization to Af in asthmatics without ABPA.
   • Preferred lab for testing is Northwestern, 240 E. Huron, McGaw, Room M-316, Chicago, IL 60611, Tel (312) 695-4000
     Fax (312) 695-4141; p-greenberger @ northwestern.edu
4. CXR should be obtained for infiltrates or bronchiectasis. A negative CXR should be followed by an HRCT scan of the chest.
   • Bronchiectasis by HRCT present in 15-18% of non-ABPA asthmatics with positive SPT to Af, however bronchiectasis by CT scan is more central and extensive in patients with ABPA (42 vs 5% of lobes in one study)
5. A positive sputum culture for Af is a helpful, but not pathognomonic, feature of ABPA
6. Peripheral eosinophilia (>1000 cell/mL) is supportive of ABPA but many do not have marked eosinophilia
7. TARC serum levels may be an accurate marker for ABPA diagnosis (also in CF patients with ABPA)

Algorithm (Slavin)

Asthma vs. ABPA

• Diagnosis of ABPA in the absence of asthma must be made with care. Consider possibility of ABPA with preclinical asthma, or ABP-mycosis which may have a different clinical course
• Asthmatics sensitized to Af but who do not have ABPA can have:
  • Positive SPT/ID to Af (20-30%)
  • Positive serum precipitins to Af (10% of asthmatics, and 10% of nonasthmatics with chronic lung disease)
  • Recurrent mucoid impaction and atelectasis
  • Peripheral blood eosinophilia and elevation of serum total IgE

CF vs. ABPA

• Both diseases may include:
  • Atopy
  • Asthma
  • Positive skin test to Af
  • Positive precipitin to Af
  • Elevated IgE
  • Pulmonary infiltrates
  • Bronchiectasis
    
    
• The diagnosis of ABPA in a patient with CF may be suggested by markedly increased peripheral blood eosinophils, serum IgE greatly elevated to levels above 1000 IU/mL, and if pulmonary infiltrates do not respond to antibiotics, are transient, and resolve with corticosteroids
• In one study, measuring Asp f 4 IgE with both ELISA and precipitin had sensitivity of 100% for detection of ABPA in CF patients

ABPM vs. ABPA

• An ABPA-like syndrome associated with fungi other than Af has been described (allergic bronchopulmonary mycosis)
• Fungi associated with ABPM include: Curvularia, Candida, Fusarium, Penicillium, Drechslera, Stemphyllium, Pseudallescheria, and Helminthosporium

Clinical Staging of ABPA

Classification-----	Description	Radiographic infiltrates	Total serum IgE
I	Acute	Upper lobes or middle lobe	Markedly elevated
II	Remission	No infiltrate; off prednisone >6 mo	Elevated or normal
III	Exacerbation	Upper lobes or middle lobe	Markedly elevated
IV	Corticosteroid-dependent asthma-----	Infiltrates absent or only intermittent----------	Elevated or normal----------
V	End stage	Fibrotic, bullous or cavitary lesions	May be normal

Treatment (Weller)

• Antifungal - adjunct to corticosteroids
  • Itraconazole - Recommended for stage I and III with the goal of enabling a reduction in the steroid dose.
    • Adults: itraconazole 200 mg TID for 3 days followed by 200 mg BID with food.
    • Children: itraconazole 5 mg/kg/d given either QD, or if the total dose exceeds 200 mg/d, divided BID with food.
    • Duration: 4 months recommended (usual range 3-6 months).
    • Liquid absorbed better than capsules but causes more GI upset; avoid acid-blocking medications with capsules.
  • Voriconazole, posiconazole, inhaled amphotericin B - limited data for ABPA

• Corticosteroids - primary treatment
  • Stage I - Prednisone 0.5-1 mg/kg for 14 days (or longer until infiltrates cleared) followed by conversion to an every other day regimen and a slow taper over 3-6 months.
    • Monitor total IgE monthly or bimonthly. Resolution of infiltrates and clinical remission (stage II) usually accompanied by >35% reduction in total IgE (patients with a baseline IgE level <2500 IU/mL may not have as large of a percentage decrease in IgE in response to steroids). An increase in serum IgE may herald or accompany lung infiltrates and peripheral eosinophilia.
  • Stage II - Steroids not indicated.
  • Stage III - Recurrent exacerbations are frequent and are accompanied by >100% rise in total IgE over baseline. Begin a tapered prednisone regimen as detailed above for stage I. 20-35% of flares are asymptomatic and are detected radiographically and serologically.
    • Chest x-rays should be obtained if signs of an asymptomatic flare are detected during exam or if a patient has an pattern of recurrent, asymptomatic flares.
  • Stage IV - Steroid-dependent asthma, patient cannot discontinue steroids without a return of asthma symptoms.
  • Stage V - Steroids not indicated.

Treatment of ABPA (Greenberger)

1. Prednisone is drug of choice; 0.5 mg/kg daily for 2 weeks, then on alternate days for 6 to 8 weeks, then attempt tapering by 5 mg on alternate days every 2 weeks. 2. Repeat CXR and/or CT lung at 2-4 weeks to document clearing of infiltrates. 3. Serum IgE concentration at baseline and at 4 and 8 weeks, then every 8 weeks for first year to establish range of total IgE concentrations (a 100% increase can identify a silent exacerbation). 4. Baseline spirometry or full pulmonary function tests depending on the clinical setting. 5. Environmental control for fungi and other allergens at home or work. 6. Determine if prednisone-dependent asthma (stage IV ABPA) is present; if not, manage asthma with anti-inflammatory medications and other medications as indicated. 7. Future ABPA exacerbations may be identified by: Asymptomatic sharp increases in the total serum IgE concentration Increasing asthma symptoms or signs Deteriorations in FVC and/or FEV1 Cough, chest pain, new production of sputum plugs, dyspnea not explained by other causes CXR or CT findings (patient may be asymptomatic) 8. Document in chart that prednisone side effects were discussed and address bone density issues (e.g., adequate calcium, exercise, hormone replacement and antiosteopenia medication if indicated). 9. Persistent sputum expectoration should be cultured to identify Aspergillus fumigatus, Staphylococcus aureus, Pseudomonas aeruginosa, atypical Mycobacteria, etc. 10. If new ABPA exacerbations occur, repeat step 1.

• Omalizumab - Reported to enable reduction in corticosteroid doses in children with CF and ABPA. May also be effective in adults with ABPA (without CF).

• Mold aeroallergen avoidance - Attempts should be made to repair leaky basement walls and floors to minimize moldy basements. Because spores of Aspergillus species, including Af, are detected regularly both indoors and outside, a common sense approach seems advisable.

• Allergen immunotherapy vs. Af relatively contraindicated due to theoretical risk of injecting Af antigen into a patient with serum precipitins to Af. Patients may receive IT to other allergens.
  • In contrast, some recommend immunotherapy for allergic fungal sinusitis

References